What is Fibrosis?

FIBROSIS

An accumulation in the liver of fibrous tissue resulting from an imbalance between production and degradation of the extracellular matrix, and accentuated by the collapse and condensation of preexisting fibers.

FIBROSIS Etiology

Fibrosis is a common response to hepatocellular necrosis or injury, which may be induced by a wide variety of agents: any process disturbing hepatic homeostasis, especially inflammation, toxic injury, or altered hepatic blood flow; and infections of the liver (viral, bacterial, spirochetal, and parasitic). Numerous storage disorders due to inborn errors of metabolism are often associated, including lipid abnormalities (Gaucher's disease); glycogen storage diseases (especially types III, IV, VI, IX, and X); alpha1-antitrypsin deficiency; storage of exogenous substances as seen in iron-overload syndromes (hemochromatosis) and in copper storage diseases (Wilson's disease); disorders resulting in the accumulation of toxic metabolites (as in tyrosinemia, fructosemia, and galactosemia); and peroxisomal disorders (Zellweger syndrome). Numerous chemicals and drugs are implicated (especially alcohol, methotrexate, isoniazid, oxyphenisatin, methyldopa, chlorpromazine, tolbutamide, and amiodarone). Vascular disorders can also cause fibrosis: obstruction to both intrahepatic and extrahepatic bile flow and various disturbances of the hepatic circulation (eg, chronic heart failure, Budd-Chiari syndrome, veno-occlusive disease, portal vein thrombosis).

FIBROSIS Pathogenesis

The normal liver is made up of hepatocytes and sinusoids distributed within a matrix composed of collagen (predominantly types I, III, and IV), noncollagen proteins including glycoproteins (eg, fibronectin and laminin), and several proteoglycans (eg, heparan sulfate, chondroitin sulfate, dermatan sulfate, and hyaluronate). Fibroblasts found in the portal tracts are the prototype for producing collagen, large glycoproteins, and proteoglycans. Other liver cells (particularly hepatocytes and endothelial, Kupffer, and fat-storing [Ito] cells) also can produce extracellular matrix components. Fat-storing cells, located beneath the sinusoidal endothelium in the space of Disse, have a fibroblast-like morphology. During fibrosis, Ito cells can proliferate and an excess of extracellular matrix components accumulate. When the liver regenerates, the Ito cells undergo transformation to myofibroblasts and alter the secretion of collagen from predominantly types III and IV to type I, the type found in most forms of cirrhosis.

Control of fibrogenesis, still poorly understood, appears to involve cell interactions in the hepatic sinusoid. Kupffer cells secrete a poorly characterized factor that may stimulate the Ito cells to produce collagen. O2-free radicals released by activated Kupffer cells and other macrophages have a similar effect. Fibroblast growth is promoted by factors released from Kupffer cells, eg, interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha) and platelet-derived growth factor (PDGF). Leukotrienes secreted by macrophages are chemotactic for other inflammatory cells whose products may promote fibrosis. Vitamin A in large doses and transforming growth factor-beta (TGF-beta) also stimulate fibrogenesis by fat-storing cells. TGF-beta, secreted by hematopoietic cells, may regulate fibrogenesis at several levels: by increase of mRNA production of procollagen and fibronectin; by production of collagenase inhibitor; and by chemotaxis of monocytes and fibroblasts. Fibrosis may derive not only from active fibrogenesis, but also from impaired degradation of normal or altered collagen. In this respect, endothelial cells, fat-storing cells, and Kupffer cells have important roles in the clearance of type I collagen, several proteoglycans, and denatured collagens. Changes in these cells' activities may modify the extent of fibrosis. Furthermore, for the histopathologist, fibrous tissue may become more apparent from passive collapse and condensation of preexisting fibers.

Thus, increased synthesis and/or reduced degradation of collagen results in active deposition of excessive connective tissue, which will affect hepatic function: (1) Pericellular fibrosis impairs cellular nutrition and hepatocellular atrophy results. (2) Within the space of Disse, fibrous tissue accumulated around the sinusoids obstructs the free passage of substances from the blood to the hepatocytes. (3) Fibrosis around hepatic venules and the portal tracts disturbs hepatic blood flow. Venous resistance across the liver increases from portal vein branches to sinusoids, and finally to hepatic veins. All 3 routes can be involved.

The fibrous bands that link portal tracts with central veins also promote anastomotic channels: Arterial blood, bypassing the normal hepatocytes, is shunted to efferent hepatic veins, which further impairs hepatic function and leads to hepatocellular necrosis. The extent to which any or all of these processes is present determines the magnitude of hepatic dysfunction; eg, in congenital hepatic fibrosis (CHF), large fibrous bands involve predominantly the portal regions but usually spare the hepatic parenchyma. CHF thus presents as portal hypertension with preservation of hepatocellular function.

FIBROSIS Diagnosis and Treatment

Although fibrosis is common to several chronic liver diseases, the clinical feature that predominantly reflects hepatic fibrosis is portal hypertension.

The histologic diagnosis depends upon examination of a liver biopsy. Special stains (eg, aniline blue, trichrome, silver stains) may highlight the fibrous tissue. Since fibrosis is a sign of hepatic injury, its management is usually directed toward the underlying cause.